Mild cognitive impairment is characterized by deficits in memory, language and/or other essential cognitive functions that do not interfere with an individual's daily life. The condition often evolves towards dementia, which is characterized by a global deterioration of cognitive abilities to an extent that does interfere with daily life. Alzheimer's disease (AD) is the most common form of dementia among older people and refers to dementia that does not have an antecedent cause, such as stroke, brain trauma, or alcohol; it is characterized by the presence in the brain of extracellular amyloid plaques and intracellular neurofibrillary tangles that provoke neuronal dysfunction and cell death. The increasing number of AD patients associated with the aging of the population makes the development of new disease management/treatment strategies critical.
The search for effective AD management has been largely based on the amyloid (Aβ) hypothesis, mainly focusing on reducing the number of senile plaques, although with little success to date. Focus is placed now on other hallmarks of the disease such as hyperphosphorylation of the cytoskeletal protein tau, which is the main component of neurofibrillary tangles.
Gene transcription and protein synthesis plays an important role in the formation of new memories. An increase in histone (H3 and/or H4) acetylation using histone deacetylase (HDAC) inhibitors induces chromatin re-structuring, which is associated with gene transcription activation. HDAC proteins are classified in four families: class I (HDAC 1-3, HDAC8), class IIa (HDAC 4, 5, 7 and 9), class IIb (HDAC 6 and 10), and class IV (HDAC 11). The expression pattern of each HDACs in the central nervous system (CNS) and its contribution in memory function varies among each subtype.
4-phenylbutyrate (PBA), a HDAC inhibitor, is an effective cognitive-enhancer in the Tg2576 transgenic mouse model of AD, which overexpresses a mutant form of the amyloid precursor protein (APP). Additionally, PBA reversed the pathological hallmarks of the disease and restored dendritic spine loss in this animal model. Taking into account that PBA inhibits HDACs class I and IIb, all these data strongly suggest the potential for therapeutic benefits of HDAC inhibitors in AD, especially for class I HDACs and HDAC6. Class I HDAC inhibitors enhance memory function by increasing histone acetylation levels, which facilitates gene transcription in the brain. Moreover, HDAC6 inhibitors induce tubuline acetylation (AcTub) that may help cytoskeleton stability and protein traffic. This could play an important role in misfolding protein disorders, such as AD, in which HDAC6 inhibitors have been shown to reduce amyloid precursor protein processing (APP) by reducing its amyloid precursor (C99) production.
Moreover, aging is associated with an increase in phosphodiesterase (PDE) expression and activity. Thus, phosphosdiesterases (PDEs) are good candidates for non-amyloid targets in cognition deficits in general and in AD in particular. Rolipram, which is a specific PDE4 inhibitor, was the first that proved useful in restoring cognition deficits in animal models of AD.
Specific phosphodiesterase (PDE) inhibitors (e.g. PDE5 inhibitors: Sildenafil, or Tadalafil; and, PDE9 inhibitor: PF-4447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one)) have been shown to improve memory performance or/and enhance synaptic plasticity and cognitive function in different animal models of AD. PDE inhibitors regulate signalling pathways by elevating levels of cAMP and/or cGMP, which may ultimately promote gene transcription by directly and/or indirectly activating the cAMP response element-binding (CREB). CREB-dependent gene expression underlies long-term memory formation and persistent long-term potentiation (LTP), which are indicators of synaptic plasticity and strength. In the hippocampus, this probably occurs through the formation of new synaptic connections, which are needed to restore cognitive deficits. Thus, by activating the CREB signalling pathway, PDE inhibitors may ameliorate AD symptoms. Moreover, other CREB-independent mechanisms seem to act in synergy to restore cognitive impairment in AD via increase of cAMP and/or cGMP levels. Cognitive performance may be also improved indirectly by means of PDE-inhibitor-mediated increase of cerebral blood flow and/or of brain glucose consumption.
Besides amyloid burden, Tau phosphorylation is another histopathological marker of AD progression. Importantly, it has been shown that the PDE5 inhibitors Sildenafil and Tadalafil, reduce Tau phosphorylation (pTau levels) in different animal models of AD.
Therefore, there is still a need of developing compounds which show improved activity in the treatment and/or prevention of neurological disorders coursing with a cognition deficit or impairment, or neurodegenerative diseases.
Document WO 2008/024494 discloses compounds having an imidazo[5,1-f][1,2,4]triazin-4-one core, which are PDE5 inhibitors. In particular, it discloses compound 14 (page 70), which has an imidazo[5,1-f][1,2,4]triazin-4-one core and a hydroxamic acid ester. This compound, hereby referred as comparative example 2-01, was synthethized by the present inventors and as shown in the examples below, it was inactive against HDAC1, HDAC2 and HDAC6; IC50>20 μM.
Document WO 2012/020022 discloses 6-cycloalkyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one derivatives and their use as PDE9A inhibitors. In particular, it discloses in example 8B (page 77) a compound with a 1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one core and a hydroxamic acid ester. This compound, hereby referred as comparative example 3-01, was synthethized by the present inventors and as shown in the examples below, it was inactive against HDAC1, HDAC2 and HDAC6; IC50>20 μM.